Field of the Invention
The present invention relates to a method for production of nucleoside derivatives by selective hydrolysis.
Deoxynucleosides (III) through (VI), 2'-fluoro-2',3'-dideoxynucleosides (VII), 3'-fluoro-2',3'-dideoxynucleosides (VIII) and 2',3'-dideoxynucleoside derivatives shown by structural formula (IX) are obtained through selective hydrolysis: ##STR1## wherein B represents a nucleoside base; R.sup.1 and R.sup.2 are hydrolyzable acyl groups having 1 to 12 carbon atoms and R.sup.3 represents a hydrolyzable acyl group having 1 to 12 carbon atoms or hydrogen; and X is a hydrogen atom, halogen atom, alkyl group having 1 to 12 carbon atoms or an acyloxy group having 1 to 12 carbon atoms.
The present nucleoside derivatives are known compounds which have antiviral activity or are useful as synthetic intermediates thereof (cf., for example, H. Mitsuya and S. Broader, Proc. Natl. Acad. Sci. USA, 83, 1911, 1986). Discussion of the Background
Extensive investigations have been made on synthetic reactions having high selectivity using cyclodextrin, which catalyzes bond cleavage reactions such as ester hydrolysis, amide hydrolysis, decarbonation, etc. Cyclodextrin forms a molecular complex with a reaction substrate and its chemical reaction proceeds as an interaction within the molecular complex. Therefore, cyclodextrin has been widely used as an enzyme model. The interaction between nucleotide and cyclodextrin has also been studied (Hoffmann et al., Biochemistry, 1970, 9, 3542). Komiyama et al. made further studies on the molecular complex between nucleoside and cyclodextrin and found a regioselective cleavage of 2',3'-cyclic monophosphate at the 2'-position by the catalyzing action of .alpha.-cyclodextrin (J. Am. Chem. Soc., 111, 3046, 1989). Recently, Uemura et al. found regioselective acylation of thymidine derivatives by enzyme. As described above, selective hydrolysis of nucleoside derivatives has become a target of important studies in recent years, not only in the field of synthetic chemistry but also in the fields of biochemistry and genetic engineering.
Deoxynucleosides (V) and (VI), 2'-fluoro-2',3'-dideoxynucleosides (VII) and 3'-fluoro-2',3'-dideoxynucleosides (VIII) and the 240 ,3'-dideoxynucleoside derivatives shown by formula (IX), described above, can be utilized as drugs for the treatment of AIDS, etc., so that keen attention has been paid to the compounds as having an antiviral activity (cf., Japanese Patent Application Laid-Open No. 61-280500 and J. Med. Chem., 30, 440 (1987)).
As a method for production of these nucleoside derivatives, for example, with respect to 3'-deoxynucleosides (V), there is known the method of Reese et al. (Synthesis, 304, 1983) which comprises subjecting 2'-acetyl-3'-bromoadenosine to radical reduction. With respect to 2'-deoxynucleosides (VI), the method of Todd et al. (J.C.S., 3035, 1958) is known. Further with respect to 2'-fluoro-2',3'-dideoxynucleosides (VII) and 3'-fluoro-2',3'-dideoxynucleosides (VIII), where is known a method for producing .alpha.-compounds which comprises fluorinating the hydroxy group of the nucleosides with inversion and subjecting the remaining hydroxy group to radical reduction; and regarding .beta.-compounds, there has been found a method which comprises glycosylation of fluorinated sugar and nucleoside base (these methods are described in Biochemical Pharmacology, 36, 2719, 1987), and a method for synthesis which comprises treating 5'-tritylcordycepin (3-deoxyadenosine) with DAST (J. Med. Chem., 30, 2131, 1987), etc.
As methods for synthesis of the 2',3'-dideoxynucleoside derivatives (IX), there are known methods involving radical reduction (J. Med. Chem., 30, 862, 1987) or photoreduction (J. Am. Chem. Soc., 108, 3115, 1986); a method by applying olefination of diol (Corey-Winter reaction, J. Org. Chem., 54, 2217, 1989; Eastwood reaction, J. Org. Chem., 53, 5179, 1988), a method which comprises synthesis of dideoxy sugar followed by glycosylation (from glutamic acid, Tetrahedron Lett., 29, 1239, 1988; from D-mannitol, Nucleosides, Nucleotides, 903, 1989). As another important route, there is known a method using nucleoside derivatives having an acyloxy group and a halogen atom at the 2'- and 3'-positions (or at the 3'- and 2'-positions) as intermediates. The compounds are synthesized by the method of Moffatt et al. (J. Am. Chem. Soc., 95, 4025, 1973; U.S. Pat. No. 3,658,787 or J. Org. Chem., 39, 30, 1983); the method of Robins et al (J. Am. Chem. Soc., 98, 8213, 1976); the method of Engels (Tetrahedron Lett., 21, 4339, 1980); the method of Reese et al. (Synthesis, 304, 1983); the method disclosed in Japanese Patent Application Laid-Open No. 1-224390 which is a prior copending application filed by the same applicant. For synthesis of 2',3'-dideoxynucleoside derivatives from the nucleoside derivatives, there is known a method of direct reduction using a palladium catalyst or a method via olefins (Moffatt et al., J. Org. Chem., 39, 30, 1974; U.S. Pat. No. 3,817,982; Robins et al., Tetrahedron Lett., 367, 1984).
As described above, various methods for synthesis of the 2',3'-deoxynucleoside derivatives (V) have been developed but involve the following problems:
(a) expensive reactants are used; PA1 (b) many products are formed; PA1 (c) many reaction steps are involved; PA1 (d) upon scaling up, problems are involved in operations of the reaction or treatment.
Therefore, it has been desired to develop an excellent method for synthesis of them.